NATIONAL HARBOR –  Mesenchymal stem cell transplantation reduced opioid tolerance and opioid-induced hyperalgesia caused by daily morphine injections in a rat study, which was presented this weekend at the 31st Annual Meeting of the American Academy of Pain Medicine. 

The results could herald stem cell transplantation as an innovative, safe, efficacious and cost-effective therapy to treat pain and opioid tolerance, said Kathleen Cheng, who presented the results on behalf of the Cleveland Clinic in a Plenary Research Highlight session. 

Not only was opioid tolerance prevented when the rats were transplanted with mesenchymal stem cell transplantation (MSC) before repeated morphine injections, but tolerance was reversed when the rats were treated after opioid tolerance had developed, results demonstrated. 

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Cheng noted that MSCs have a known anti-inflammatory effect. MSCs can differentiate into a variety of cell types and have been investigated for potential repair of damaged neural cells and for calming inflammation in the immune system to promote recovery after traumatic brain injury.

Following this line of research, the study investigators wondered whether they could create an anti-tolerance therapy by transplanting MSCs into the intrathecal space surrounding the spinal cord. 

With approval by the Cleveland Clinic Institutional Animal Care and Use Committee and funding through the Department of Defense’s Congressionally Directed Medical Research Programs, they compared the withdrawal thresholds of the hind paws in response to painful mechanical and thermal stimuli in two groups of rats that received daily morphine injections. 

The first group was treated with MSC transplantation and the control group with phosphatebuffered saline (PBS). They found that both groups of rats developed morphine tolerance (ie, reduced responsiveness to morphine) within five to seven days with repeated injections; however, the MSC group demonstrated significant and consistent higher thresholds for paw withdrawal than the PBS group. 

Furthermore, immunohistochemistry confirmed microglial activation in the spinal cord after repeated daily morphine injections, but the activity was substantially weakened in rats treated with MSC. The animals also maintained normal locomotion, food and fluid intake and body weight gain, findings that demonstrated safety, Cheng said. 

The next step, she said, is to translate the experience of animal experiments to clinical trials. Cheng outlined the need to first determine and optimize the key variables of stem cell transplantation, such as sources of cells, routes of administration, number of cells to transplant and the timing of transplantation.

She characterized the procedure as practical, in light of readily available sources of stem cells, reliable stem cell technology, the simplicity of transplantation procedures and the fact that clinical trials are already underway involving autoimmune and other diseases. 


1. Cheng K, et al. Poster 181. “Stem Cell Transplantation-Inhibited Microglial Activation and Reversed MorphineInduced Opioid Tolerance in Rats.” Presented at: AAPM 2015. March 19-22, 2015; National Harbor, Maryland.